Well-known antimicrobial compositions include conventional treatments such as antiseptics and antibiotics. Other treatments include silver-containing gels, compounds containing heavy metals and solutions of hydrogen peroxide and natural and synthetic pharmaceutically active substances. However, treatments such as antibiotics have disadvantages because of the emergence of antibiotic resistance. Furthermore, high levels of hydrogen peroxide have a toxic and irritant effect. In addition, hydrogen peroxide in solution is typically unstable and it is difficult to provide a sustained delivery system for this material. Additionally, there are a number of naturally occurring antimicrobial systems known which rely on the ability of certain oxidising agents to disrupt metabolic processes of bacteria, fungi and viruses. Thus, for a wide variety of different reasons, conventional antimicrobial treatments have many drawbacks.
Onychomycosis is a fungal nail infection that accounts for approximately 50% of all nail disorders and affects toenails substantially more than fingernails. The prevalence of onychomycosis has been estimated at around 3% in Western countries and has continued to increase in recent decades.
Onychomycosis may be caused by several causal agents including dermatophytes, yeasts or moulds. It is accepted that dermatophytes are by far the predominant pathogens and probably account for more than 85% of all cases of fungal nail infections. Of the dermatophytes the most common cause of onychomycosis is Trichophyton rubrum. Aspergillus niger has also been found to be another causal agent of onychomycosis. Causative fungi include Scopulariopsis brevicaulis and Scytaldium dimidiatum. 
Distal and lateral subungual onychomycosis (DLSO) is the commonest type of onychomycosis. Infection is initially a disease of the hyponychium, resulting in hyperkeratosis of the distal nail bed. It generally begins at the lateral edge of the nail rather than the central portion and spreads progressively proximally down the nail bed producing hyperkeratosis and thus onycholysis. Ultimately the underside of the nail is involved which results in thickening of the nail. The nail may become friable and crumbles away. Sometimes the fungus proliferates in the space between the nail plate and nail bed (known as a dermatophytoma) and is often the cause of treatment failure.
It is important to treat onychomycosis, as it is an infection and does not resolve spontaneously. The infection may worsen, spread to other uninfected locations (other nails or to the surrounding skin) or infect other people. Infections of the fingernails may be cosmetically unacceptable. Infections of the toenail can greatly affect the quality of life of patients and cause pain and morbidity.
Current treatments for onychomycosis include topical or oral treatments. There are four main oral therapies available for the treatment of onychomycosis. These are Griseofulvin (Grisovin®, Glaxo Wellcome) Ketoconazole (Nizoral®, Janssen-Cilag), Itraconazole (Sporanox®, Janssen-Cilag) and Terbinafine (Lamisil®, Novartis). Griseofulvin has been available since the 1950's and due to its fungistatic activity against dermatophytes requires long treatment periods, approximately 9 to 12 months for toenail infections, with low cure rates and high relapse rates. Ketoconazole was the first imidazole introduced for the treatment of onychomycosis in the 1980's. However, due to hepatotoxicity its use is now restricted to fingernail infections that have failed to respond to other therapies. The newer antifungals, Itraconazole and Terbinafine, are highly effective in the treatment of onychomycosis with mycological cure rates of 70-80% and treatment periods of 12 to 16 weeks. Topical therapies include Amorolfine (Loceryl®, Galderma) and Ciclopirox (Penlac®, Dermik). Probably as a result of the poor drug penetration from these products through the nail, treatment times are long, approximately 12 months for toenail infections, and cure rates are low, Thus, alternative drugs and formulations to improve delivery are being sought.
Drug delivery to the nail (ungual delivery) is complicated by the physical structure of the nail. The nail apparatus is composed of the nail folds, nail matrix, nail bed and the nail plate. The nail plate, produced mainly by the matrix, emerges via the proximal nail fold and is held in place by the lateral nail folds. It overlays the nail bed and detaches from the latter at the hyponychium.
The nail plate is a thin, hard, yet slightly elastic, translucent convex structure and is made up of approximately 25 layers of dead keratinised cells which are tightly bound to one another by numerous intercellular links. Chemically, the nail plate consists mainly of the fibrous proteins, keratin, 80% of which is the ‘hard’ hair-type keratin, the remainder comprising the ‘soft’ skin-type keratin. The keratin fibres are oriented into three layers, which are associated with the dorsal, intermediate and ventral nail layers. The hair like keratin filaments are only present in the intermediate nail layer and are oriented perpendicular to the growth axis. The nail plate is formed by the nail matrix, which is a highly proliferative epidermal tissue. Cell division of the nail matrix results in the continuous formation of the plate, which grows throughout life. The growth rate is highly variable among individuals; with average values of 3 μm per month for finger nails and 1 μm per month for toe nails. The growth is also highly affected by age, gender, climate, trauma, disease and drug intake. As well as growing in length, nail plates also grow thicker as they progress from the lunula to the free margin.
The table below shows a comparison of the chemical composition of the nail plate and the Stratum corneum (outer layer of the epidermis).
CharacteristicNailStratum corneumThickness50-1000 m10-40 mDi-sulphide linkage10.60%    1.20%Lipid content0.1-1% 10-20%Water content 9-35%    25%Maximum swelling  25%200-300%Water loss1.94 mg/cm2/h0.56 mg/cm2/h
In comparison to the thin Stratum corneum, the much thicker nail plate means a much longer diffusional pathway for drug delivery. In addition, in contrast with the elastic and pliable Stratum corneum, the nail plate is dense and hard. When the thickness difference is taken into consideration, the water permeation rate of the nail is approximately 10 times higher than that of the Stratum corneum. As such it would be expected that the permeation characteristics of the nail are very different from the Stratum corneum, the main differences being detailed below:                The nail does not act like a lipoidal barrier but like a hydrophilic gel membrane;        Disulphide bonds are responsible for toughness of nail and its barrier properties;        Aqueous pathways play a more dominant role in drug permeation across the nail; and        Penetration enhancers (e.g. keratolytic and mucolytic agents) are generally required and are different for the nail.        
These differences between the nail and Stratum corneum, both physical and chemical, are probably the reasons for the lack of efficacy of topical nail antifungal formulations presently on the market. Thus, when designing topical formulations for perungual drug absorption, it is essential to consider the physicochemical properties of the drug molecule (e.g. size, shape, charge log P etc), the formulation characteristics (e.g. vehicle, drug concentration), possible penetration enhancers, as well as any possible interactions between the drug and keratin.
To date, conventional topical treatments for fungal nail infections all have significant limitations and have largely been unsuccessful.
In addition, designing alternative treatments has been problematic due to the chemical composition of the nail.
Thus, the present invention is directed to providing an alternative treatment for fungal nail infections.